We have recently discovered that a single transcription, PLZF, controls the development of the innate effector functions that are characteristic of invariant natural killer T cells (iNKT cells). iNKT cells are extremely potent "first responders" to infection. The aggressive nature of innate T cells has also made them attractive targets for immunotherapy;several clinical trials are in progress. Intriguingly, iNKT cells have antagonistic functions, since they have both been shown to enhance immunity in some circumstances, but to suppress autoimmunity in others. Indeed, at least one published report shows that specific activation of iNKT cells protects mice against colitis. In the systemic immune system, expression of the innate T cell determinant, PLZF, is nearly exclusively restricted to iNKT cells. For example, the transcription factor is not expressed in resting, activated or differentiated conventional T cells, NK cells, B cells, macrophages, neutrophils or eosinophils. In sharp contrast, in the gut, PLZF is expressed in a variety of different lymphocytes including CD8aa T cells, CD4CD8a T cells and ?d T cells. Interestingly, many of the CD8 T cells are restricted to MHC class Ib (non-classical) MHC molecules. Most significantly, CD8aa T cells isolated from the guts of PLZF deficient mice produced large amounts of IFN-? following activation. The same lymphocytes harvested from wild type mice produced little IFN? Altogether, these results strongly suggest a dominant role for PLZF expression in the maintenance of the immunoregulatory tone of the intestine and in the prevention of Th1 responses that may lead to chronic inflammation. They also suggest that PLZF expression may be conferring the innate cytotoxic capabilities to type-b a[unreadable] and ?d IELs which is essential for the clearance of infected and transformed epithelial cell and, therefore, for maintaining the integrity of the epithelial barrier. We propose a series of experiments aimed at gaining a better understanding of the consequences of PLZF expression in lymphocytes in the intestinal mucosa in normal and pathological conditions. Recently we discovered that a single transcription factor, PLZF, controls the functions of a subpopulation of T cells known as Natural Killer T cells (NKT cells). NKT cells are of great interest because they are very potent first responders to infection. They also have been shown to control autoimmunity by modulating the functions of other cells of the immune system. Our preliminary data strongly suggests that lymphocytes expressing PLZF play a major role in maintaining the immunoregulatory tone of the intestine and in the preventing the type of immune responses that may lead to chronic inflammation. Our proposed studies will offer novel insight into mucosal immunity and very likely will provide new targets for therapeutic intervention.